Modulation and analysis of cerebral perfusion in epilepsy and other neurological disorders

ABSTRACT

A system including an implantable neurostimulator device capable of modulating cerebral blood flow to treat epilepsy and other neurological disorders. In one embodiment, the system is capable of modulating cerebral blood flow (also referred to as cerebral perfusion) in response to measurements and other observed conditions. Perfusion may be increased or decreased by systems and methods according to the invention as clinically required.

CLAIM OF PRIORITY AND RELATED APPLICATIONS

This is a divisional of application Ser. No. 11/404,579, now U.S. Pat.No. 7,819,812 filed Apr. 14, 2006, which is a continuation-in-part ofapplication Ser. No. 11/014,628, filed Dec. 15, 2004, now U.S. Pat. No.7,341,562, each of which applications are incorporated by referenceherein in the entirety.

BACKGROUND

1. Technical Field

The invention relates generally to medical devices for treatingneurological disorders such as epilepsy, and more particularly to asystem incorporating an implantable device capable of measuring andmodulating cerebral blood flow.

2. Background

Epilepsy, a neurological disorder characterized by the occurrence ofseizures (specifically episodic impairment or loss of consciousness,abnormal motor phenomena, psychic or sensory disturbances, or theperturbation of the autonomic nervous system), is debilitating to agreat number of people. It is believed that as many as two to fourmillion Americans may suffer from various forms of epilepsy. Researchhas found that its prevalence may be even greater worldwide,particularly in less economically developed nations, suggesting that theworldwide figure for epilepsy sufferers may be in excess of one hundredmillion.

Because epilepsy is characterized by seizures, its sufferers arefrequently limited in the kinds of activities they may participate in.Epilepsy can prevent people from driving, working, or otherwiseparticipating in much of what society has to offer. Some epilepsysufferers have serious seizures so frequently that they are effectivelyincapacitated.

Furthermore, epilepsy is often progressive and can be associated withdegenerative disorders and conditions. Over time, epileptic seizuresoften become more frequent and more serious, and in particularly severecases, are likely to lead to deterioration of other brain functions(including cognitive function) as well as physical impairments.

The current state of the art in treating neurological disorders,particularly epilepsy, typically involves drug therapy and surgery. Thefirst approach is usually drug therapy.

A number of drugs are approved and available for treating epilepsy, suchas sodium valproate, phenobarbital/primidone, ethosuximide, gabapentin,phenytoin, and carbamazepine, as well as a number of others.Unfortunately, those drugs typically have serious side effects,especially toxicity, and it is extremely important in most cases tomaintain a precise therapeutic serum level to avoid breakthroughseizures (if the dosage is too low) or toxic effects (if the dosage istoo high). The need for patient discipline is high, especially when apatient's drug regimen causes unpleasant side effects the patient maywish to avoid.

Moreover, while many patients respond well to drug therapy alone, asignificant number (at least 20-30%) do not. For those patients, surgeryis presently the best-established and most viable alternative course oftreatment.

Currently practiced surgical approaches include radical surgicalresection such as hemispherectomy, corticectomy, lobectomy and partiallobectomy, and less-radical lesionectomy, transection, and stereotacticablation. Besides being less than fully successful, these surgicalapproaches generally have a high risk of complications, and can oftenresult in damage to eloquent (i.e., functionally important) brainregions and the consequent long-term impairment of various cognitive andother neurological functions. Furthermore, for a variety of reasons,such surgical treatments are contraindicated in a substantial number ofpatients. And unfortunately, even after radical brain surgery, manyepilepsy patients are still not seizure-free.

Electrical stimulation is an emerging therapy for treating epilepsy.However, currently approved and available electrical stimulation devicesdo not perform any detection of neural activity and apply electricalstimulation to neural tissue surrounding or near implanted electrodessomewhat indiscriminately; they are not responsive to relevantneurological conditions. Responsive stimulation, in which neurologicalactivity is detected and electrical stimulation treatment is appliedselectively, is in clinical trials at the time of this writing.

The NeuroCybernetic Prosthesis (NCP) from Cyberonics, for example,applies continuous electrical stimulation to the patient's vagus nerve.This approach has been found to reduce seizures by about 50% in about50% of patients. Unfortunately, a much greater reduction in theincidence of seizures is needed to provide substantial clinical benefit.

The Activa device from Medtronic is a pectorally implanted continuousdeep brain stimulator intended primarily to treat Parkinson's disease.In operation, it continuously supplies an intermittent electrical pulsestream to a selected deep brain structure where an electrode has beenimplanted. Continuous stimulation of deep brain structures for thetreatment of epilepsy has not met with consistent success. To beeffective in terminating seizures, it is believed that one effectivesite where stimulation should be performed is near the focus of theepileptogenic region. The focus is often in the neocortex, wherecontinuous stimulation above a certain level may cause significantneurological deficit with clinical symptoms including loss of speech,sensory disorders, or involuntary motion. Accordingly, and to improvetherapeutic efficacy over indiscriminate continuous stimulation,research has been directed toward automatic responsive epilepsytreatment based on a detection of imminent seizure.

A typical epilepsy patient experiences episodic attacks or seizures.Those events, neurological states, and epileptiform activity evident onthe EEG shall be referred to herein as “ictal.”

Most prior work on the detection and responsive treatment of seizuresvia electrical stimulation has focused on analysis ofelectroencephalogram (EEG) and electrocorticogram (ECoG) waveforms. Incommon usage, the term “EEG” is used to refer to signals representingaggregate neuronal activity potentials detectable via electrodes appliedto a patient's scalp, though the term can also refer to signals obtainedfrom deep in the patient's brain via depth electrodes and the like.Specifically, “ECoGs” refer to signals obtained from internal electrodesnear the cortex of the brain (generally on our under the dura mater),but is often used to refer to direct brain signals from deeperstructures as well; an ECoG is a particular type of EEG. Unless thecontext clearly and expressly indicates otherwise, the term “EEG” shallbe used generically herein to refer to both EEG and ECoG signals,regardless of where in the patient's brain the electrodes are located.

It is generally preferable to be able to detect and treat a seizure ator near its beginning, or even before it begins. The beginning of aseizure is referred to herein as an “onset.” However, it is important tonote that there are two general varieties of seizure onsets. A “clinicalonset” represents the beginning of a seizure as manifested throughobservable clinical symptoms, such as involuntary muscle movements orneurophysiological effects such as lack of responsiveness. An“electrographic onset” refers to the beginning of detectableelectrographic activity indicative of a seizure. An electrographic onsetwill frequently occur before the corresponding clinical onset, enablingintervention before the patient suffers symptoms, but that is not alwaysthe case. In addition, there are changes in the EEG that occur secondsor even minutes before the electrographic onset that can be identified,and may be used to facilitate intervention before clear electrographiconset or clinical onsets occur. This capability would be consideredseizure anticipation, in contrast to the detection of a seizure or itsonset. Seizure anticipation is much like weather prediction—there is anindication the likelihood has increased that a seizure will occur, butwhen exactly it will occur, or even if it will occur is not certain.

U.S. Pat. No. 6,018,682 to Rise for “Implantable Seizure WarningSystem,” issued Jan. 25, 2000, describes an implantable seizure warningsystem that implements a form of the Gotman system. See, e.g., J.Gotman, Automatic Seizure Detection: Improvements and Evaluation,Electroencephalogr. Clin. Neurophysiol. 1990; 7(4): 317-24. However, thesystem described therein uses only a single detection modality, namely acount of sharp spike and wave patterns within a limited time period, andis intended to provide a warning of impending seizure activity in spiteof a lack of evidence that spike and wave activity is sufficientlyanticipatory of seizures. This is accomplished with relatively complexprocessing, including averaging over time and quantifying sharpness byway of a second derivative of the signal. The Rise patent does notdisclose how the signals are processed at a low level, nor does itexplain detection criteria in any specific level of detail.

U.S. Pat. No. 6,016,449 to Fischell, et al., for “System for Treatmentof Neurological Disorders,” issued Jan. 18, 2000 (which is incorporatedby reference as though set forth in full herein), describes animplantable seizure detection and treatment system. In the Fischellsystem, various detection methods are possible, all of which essentiallyrely upon the analysis (in either the time domain or the frequencydomain) of processed EEG signals. Fischell's controller is preferablyimplanted intracranially, but other approaches are also possible,including the use of an external controller. The processing anddetection techniques applied in Fischell are generally well suited forimplantable use. When a seizure is detected, the Fischell system appliesresponsive electrical stimulation to terminate the seizure, a capabilitythat will be discussed in further detail below.

All of these approaches provide useful information, and in some casesmay provide sufficient information for accurate detection, and/oranticipation of most imminent epileptic seizures.

It has been found that many clinical neurological disorders areassociated with abnormal blood flow patterns in the brain. These includeepilepsy, migraine, aging, movement disorders, and psychiatricdisorders. One result of abnormal blood flow is an imbalance betweencerebral oxygen supply and demand, although other aspects, such asremoval of metabolic waste products, also contribute to generation ofthe disorders. This is thought to play an important role in thedevelopment of cerebral injury as well as generation of neurologicalevents common to various disorders. It would therefore be advantageousto employ a system or method to monitor such abnormal blood flowpatterns, either in isolation or in connection with abnormalelectrographic activity, to identify the status of the disease state andto monitor the short-term and/or long-term progression of the diseasestate with the intention of correcting the abnormal or insufficientblood flow patterns to provide clinical benefit. Such monitoring ispreferably accomplished within the therapy delivery device (often aneurostimulator) to automatically adjust therapy delivery to the patientto more optimally bring about beneficial changes in brain blood flowpatterns either acutely or more long term. Therapy delivery may bedirect brain electrical stimulation, spinal cord stimulation, brain stemor peripheral nerve stimulation, or may be magnetic stimulation,somatosensory stimulation, or drug delivery. However, monitoring mayinclude means not included in the therapy delivery device, with therapybeing adjusted by a clinician. Monitoring of the brain blood flow can beaccomplished by the periodic use of non-invasive imaging techniquesincluding SPECT, PET, SISCOM, infrared, ultrasound, or impedancetechniques.

As is well known, it has been suggested that it is possible to treat andterminate seizures by applying electrical stimulation to the brain. See,e.g., U.S. Pat. No. 6,016,449 to Fischell et al., and H. R. Wagner, etal., Suppression of Cortical Epileptiform Activity by Generalized andLocalized ECoG Desynchronization, Electroencephalogr. Clin.Neurophysiol. 1975; 39(5): 499-506. It has further been found thatelectrical stimulation can modulate blood flow in the brain. It has beenfound that cortical stimulation increases blood flow within hundreds ofmilliseconds at the site of stimulation (T. Matsuura et al.,Hemodynamics Evoked By Microelectrical Direct Stimulation In Ratsomatosensory Cortex, Comp. Biochem. Physiol. A. Mo. 1 Integr. Physiol.(1999) September; 124(1): 47-52; see also S. Bahar et al., TheRelationship Between Cerebral Blood Volume and Oxygenation FollowingBiPolar Stimulation of the Human Cortex: Evidence for an Initial Dip,AES December 2004 New Orleans Poster Session). Stimulation of otherbrain structures or through the use of transcranial magnetic stimulationcan produce patterns of blood flow changes (including increases orreductions of blood flow) in targeted areas.

At the current time, there is no known implantable device that iscapable of treating abnormal neurological conditions, includingseizures, by changing cerebral perfusion either acutely or chronically.Furthermore, there is no known implantable device that is capable ofdetecting and/or anticipating seizures or other neurological eventsbased on cerebral perfusion conditions and changes therein, alone or incombination with other observed conditions. As anticipated herein,modulation of blood perfusion in the brain may be employed for acute orchronic treatment of neurological conditions.

SUMMARY

A system according to the invention includes an apparatus, preferablyimplantable, capable of modulating cerebral blood flow and/or sensingchanges in cerebral blood flow, either globally or locally, andresponding thereto to achieve acute and/or chronic changes in cerebralblood flow.

The invention provides for the use of electrical stimulation and othermodalities of stimulation (including transcranial magnetic stimulation)directed at a variety of anatomical targets to produce changes inperfusion and cortical blood flow to treat neurological disorders,including but not limited to epilepsy. Stimulation may be applied “openloop” (on a scheduled basis), or “closed loop” as a result ofinformation from sensors, particularly blood flow, electrographic, ormovement sensors. Therapy may also be provided on command by aphysician, the patient, or a caregiver. Systems according to theinvention may be adapted for implantable use, or may be partially orcompletely external to the patient.

Evaluation of perfusion, and also the modulation of perfusion, refersnot simply to the general passage of fluid through the blood vessels tosupply neural tissue, but also to the adequacy of the blood supplyrelative to the needs of the brain or relative to the symptoms of adisorder for which stimulation serves as treatment. Methods such asoptical spectroscopy provide measures not only related to activation,but the individual concentrations of both oxyhemoglobin (HbO₂) anddeoxyhemoglobin (HbR) result from a combination of physiological factorssuch as regional blood volume, blood flow, oxygen consumption, and wasteproduct removal. The accumulation of HbO₂ in the brain is also dependenton both arterial inflow and venous outflow of a region. Rather thansimply a form of circulation or hemodynamic monitoring, permitted bymeasurement or inference of the general perfusion of a region of tissue(e.g., various types of flowmetry), perfusion, here, includes aconsideration, in the context of blood supply, of tissue's sensitivityto brain activation and oxygen levels, or, even more specifically,relative changes in brain activation and oxygen levels. Perfusion,therefore, includes the supply and demand aspects of blood flow, volume,and constituents with respect to the disorder and its treatment.Cerebral perfusion should be understood to relate to any aspect ofproviding tissue with sufficient blood to function in a healthy fashionwhile also removing waste products of cellular activity. Cerebralperfusion status is determined by, and may refer to, any of thefollowing: cerebral blood volume, cerebral blood flow, blood gascomposition, indexes of blood gas composition such as HbO₂/(HbO₂+Hb), orHb_(T) (Hb_(total)), arterial oxygen content, venous oxygen content(which can be determined, for example, by locating two sensorsappropriately) or others as are known to those skilled in the art.

Conceptually tissues or brain regions which can serve as neural targetsfor providing therapy can be classified as “associated” or“non-associated.” Associated tissue is relatively related to a symptomof the disorder. For example, associated tissue may be a region relatedto the focus of seizure origin, or a region with abnormal metabolicactivity which is related to the disorder. Non-associated tissue may bea region which is relatively less modulated by the disorder, compared toassociated tissue, such as an area which is distal to a seizure focus,or an area of normal or abnormal metabolic activity which is relativelyunrelated to, or unaffected by, the disorder. While the likelihood ofbeing non-associated tissue generally increases as distance from anassociated region increases, due to the tract and networks of the brain,measures such as covariance rather than proximity, relate more towhether a region adjacent to an associated area are also defined assuch.

Electrical stimulation may be applied directly to the cortex, oralternatively to deeper brain structures, or to the brain stem, spinalcord or to cranial or peripheral nerves. Electrical stimulation, when itis applied, may be pulsatile in nature or of an arbitrary waveformincluding sine waves. Different stimulation patterns, and the locationof the stimulation, may be varied depending upon the brain state. Forexample, a hypo-perfused seizure onset focus in the interictal state mayreceive a stimulation pattern specifically designed to maximize bloodflow. As the brain transitions into a pre-seizure state as determined bycharacteristic changes in blood flow, electrographic evidence, or evenby the patient feeling symptoms and communicating the information to thetherapy device, the stimulation pattern may be beneficially changed toenhance blood flow in neural pathways (for instance in those pathwaysemanating from the seizure focus), or to decrease excitability at theseizure focus for example by stimulation of the caudate.

One system according to the invention includes an implanted controlmodule, controllable via external equipment, that is capable of applyingtherapeutic intervention to alter cerebral blood flow via electrical,thermal, chemical, electromagnetic, or other therapy modalities setforth herein and described in greater detail below. Preferably, suchstimulation is not provided continuously, but intermittently, and meansare provided to verify the need and/or effects of blood flow stimulationaccording to the invention. For example, an external programmer may beused to command the implanted device to deliver stimulation, after whichmeasurements are taken (via imaging techniques or other methodsdescribed herein, including automatic measurements taken by theimplanted device) to verify the effects or progress of the therapy.Depending on the effects observed, the implanted device is programmed bythe external programmer with a preferred therapy regimen.

In an embodiment of the invention, automatic measurements are taken bythe implanted device via impedance plethysmography techniques. Thesemeasurements are recorded and later transferred to the externalprogrammer via wireless telemetry, and may be used by a clinician totailor therapy to the specific patient being treated.

In an embodiment of the invention, automatic measurements are taken bythe implanted device via impedance plethysmography techniques. Thesemeasurement are recorded and later transferred to the externalprogrammer via wireless telemetry, and may be used by a clinician totailor therapy to the specific patient being treated.

A specific embodiment of a system according to the invention performsregular perfusion measurements and applies therapy automatically inresponse thereto. This embodiment includes an implanted control module,implanted electrodes on a seizure focus and on the caudate nucleus, andan implanted pulse oximetry perfusion sensor in the vicinity of theseizure focus. In addition, a perfusion sensor (with electrodes) may beimplanted on the contralateral lobe from the seizure focus. Afterimplant, baseline perfusion and electrographic data may be collected forat least several days and for several seizures while the patientrecovers from surgery. Commanded stimulation studies may be performed toassess the affect of different stimulation parameters at the seizurefocus and at the caudate on perfusion behavior. Stimulation at theseizure focus will generally increase perfusion (the seizure focus isgenerally hypo-perfused in the interictal period) whereas stimulation ofthe brain stem structures or the caudate may decrease perfusion.

The implanted control module monitors perfusion at the epileptogenicfocus, taking pulsed measurements periodically, for example, every 30seconds to save power. If sudden changes in perfusion are detected, thesampling rate (or other aspects of the sensing procedure) may beincreased for improved resolution. The control module runs a therapyalgorithm to increase the perfusion level at the epileptogenic focus toa target range by applying stimulation as programmed within a presetrange of allowed parameters (pulse amplitude, pulse width, number ofpulses in a burst, pulse to pulse interval, interval between bursts,rate of change allowed from burst to burst). If the perfusion level inthe area of the seizure focus increases above the target range, thealgorithm calls for the control module to stimulate other brainstructures such as the caudate or structures in the contralateralhemisphere in an attempt to bring the perfusion level down to a targetrange (this target range may be different than the target used whenstimulating the focus directly). Alternatively, tissue near the focus,but which does not participate in the seizure, may be stimulated inorder to decrease blood flow to the focus. Activating adjacent tissuethat is perfused by a vascular branch that can compete with the branchsupplying the seizure focus may be such an alternative target. Thepatient or a caregiver may be alerted if a trend towards increasedperfusion of the epileptogenic focus occurs despite caudate stimulation.This would allow the use of an increased dose of antiseizure medicationonly when a breakthrough seizure is likely to occur.

Episodes of disorders such as migraine are progressive in that thesewill typically follow a sequence of events, for example, aura,uncomfortable pressure, headache, and allodynia. These can berepresentative of different biological events which also can occursequentially, such as, hypothetically, spreading depression,activation/sensitization of the trigeminovascular system,vasodilation/neurogentic inflammation, and central modulation ofmigraine pain. The observation that disorders such as migraine aresequential, or at least have stages, is evident in differential responseto triptan intervention, where its provision early during an attackprovides much greater benefit, specifically when it is provided prior tothe emergence of allodynia. Epileptic seizures are also generallysequential, but with a different sequence of steps. Accordingly,neurostimulation treatment during a disorder is advantageously modifiedaccording to what stage of the disorder is occurring and the timetherapy is being applied. In one embodiment, sensed data, such asnear-infrared spectroscopy (NIRS) data, is used to automatically providean estimate of which step of a migraine sequence is occurring. Thecorresponding therapy parameters are then selected (for example, via alook-up table). Further, or as an alternative to using sensed data, whenusing an external patient programmer or other apparatus capable oftransmitting information to the neurostimulator device, the patient caninput information which can assist in determining which step in asequence of steps is occurring. For example, if the patient indicatesthat allodynia is occurring, the neurostimulation treatment deliveredbefore and after its manifestation can use different parameters andmodalities, and further can be directed towards different structures inthe brain. Additionally, the elapsed time from the beginning of anevent, or from a symptom of the event (as indicated by sensed data orpatient input) can also be used to provide stimulation parameters whichare appropriate for the “predicted” step of the sequence.

It should be noted that epilepsy, migraine, and other neurologicaldisorders treatable by a system according to the invention, vary greatlyin symptomology and treatment strategies from patient to patient. Togive one example, although perfusion has generally been observed to bepathologically low and increase just prior to an epileptic seizure, thereverse may be true in some patients or in some anatomical locations.Accordingly, the present invention as described in detail hereinprovides a framework for the diagnosis and treatment of neurologicaldysfunctions by sensing and responding to changes in cerebral bloodflow, but specific treatment strategies could be determined, customized,and altered as clinical observations and experience dictate.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects, features, and advantages of the invention willbecome apparent from the detailed description below and the accompanyingdrawings, in which:

FIG. 1 is a schematic illustration of a patient's head showing theplacement of an implantable neurostimulator according to an embodimentof the invention;

FIG. 2 is a schematic illustration of a patient's cranium showing theimplantable neurostimulator of FIG. 1 as implanted, including leadsextending to the patient's brain;

FIG. 3 is a block diagram illustration a system context in which animplantable neurostimulator according to the invention is implanted andoperated;

FIG. 4 is a block diagram illustrating the major functional subsystemsof an implantable cerebral blood flow modulation device according to theinvention;

FIG. 5 is a block diagram illustrating the major functional subsystemsof an implantable responsive blood flow modulation device according tothe invention;

FIG. 6 is a block diagram illustrating the functional components of thedetection subsystem of the implantable device shown in FIG. 4;

FIG. 7 is a block diagram illustrating the functional components of thetherapy subsystem of the implantable device shown in FIG. 4;

FIG. 8 is a schematic cutaway diagram of an optical sensing andstimulation probe according to the invention;

FIG. 9 is a schematic cutaway diagram of a thermographic sensing andstimulation probe according to the invention;

FIG. 10 is a schematic cutaway diagram of an ultrasonic sensing andstimulation probe according to the invention;

FIG. 11 is a schematic cutaway diagram of an electromagnetic sensing andstimulation probe according to the invention;

FIG. 12 is a schematic cutaway diagram of an electrochemical sensingprobe according to the invention;

FIG. 13 is a schematic cutaway diagram of an electrical sensing andstimulation lead according to the invention;

FIG. 14 is an exemplary graph of cerebral blood flow measurements inrelation to thresholds calculated according to the invention;

FIG. 15 is a flow chart illustrating an exemplary sequence of stepsperformed in measuring cerebral blood flow and responding to treatepilepsy and other disorders according to the invention; and

FIG. 16 is an exemplary graph of cerebral blood flow measurements inrelation to dynamically altered threshold and guard bands calculatedaccording to the invention.

DETAILED DESCRIPTION

The invention is described below, with reference to detailedillustrative embodiments. It will be apparent that a system according tothe invention may be embodied in a wide variety of forms. Consequently,the specific structural and functional details disclosed herein arerepresentative and do not limit the scope of the invention.

FIG. 1 depicts an intracranially implanted neurostimulator device 110according to the invention, which in one embodiment is a smallself-contained responsive neurostimulator located under the patient'sscalp 112. As the term is used herein, a responsive neurostimulator is adevice capable of detecting or anticipating neurological events such asictal activity, and providing therapy to neural tissue in response tothat activity, where the therapy is specifically intended to terminatethe ictal activity, treat a neurological event, prevent an unwantedneurological event from occurring, or lessen the severity, frequency orlikelihood of certain symptoms of a neurological disorder. As disclosedherein, the responsive neurostimulator detects ictal activity by systemsand methods according to the invention.

Preferably, an implantable device according to the invention is capableof detecting or anticipating any kind of neurological event that has arepresentative signature. Examples of such signatures may include acondition of a signal related to a specific waveshape, spectralcomposition, topological distribution with respect to timing, strengthor other features; and the signal can be derived from one or moreelectrical, chemical, or other sensors. While the disclosed embodimentis described primarily as responsive to epileptic seizures, it should berecognized that it is also possible to respond to other types ofneurological disorders, such as movement disorders (e.g., the tremorscharacterizing Parkinson's disease), migraine headaches, chronic pain,and neuropsychiatric disorders such as schizophrenia,obsessive-compulsive disorders, and depression. Preferably, neurologicalevents representing any or all of these afflictions can be detected whenthey are actually occurring, in an onset stage, or as an anticipatoryprecursor before clinical symptoms begin.

In the disclosed embodiment, the neurostimulator is implantedintracranially in a patient's parietal bone 210, in a location anteriorto the lambdoid suture 212 (see FIG. 2). It should be noted, however,that the placement described and illustrated herein is merely exemplary,and other locations and configurations are also possible, in the craniumor elsewhere, depending on the size and shape of the device andindividual patient needs, among other factors. The device 110 ispreferably configured to fit the contours of the patient's cranium 214.In an alternative embodiment, the device 110 is implanted under thepatient's scalp 112 but external to the cranium; it is expected,however, that this configuration would generally cause an undesirableprotrusion in the patient's scalp where the device is located. In yetanother alternative embodiment, when it is not possible to implant thedevice intracranially, it may be implanted pectorally (not shown), withleads extending through the patient's neck and between the patient'scranium and scalp, as necessary.

It should be recognized that the embodiment of the device 110 describedand illustrated herein is preferably a responsive neurostimulator fordetecting and treating epilepsy by detecting seizures or their onsets orprecursors, preventing and/or terminating such epileptic seizures, andresponding to clusters of therapies as described herein.

In an alternative embodiment of the invention, the device 110 is not aresponsive neurostimulator, but is an apparatus capable of detectingneurological conditions and events and performing actions in responsethereto. The actions performed by such an embodiment of the device 110need not be therapeutic, but may involve data recording or transmission,providing warnings to the patient, providing information to an externaldevice, or any of a number of known alternative actions. Such a devicewill typically act as a diagnostic device when interfaced with externalequipment, as will be discussed in further detail below.

The device 110, as implanted intracranially, is illustrated in greaterdetail in FIG. 2. The device 110 is affixed in the patient's cranium 214by way of ferrule 216. The ferrule 216 is a structural member adapted tofit into a cranial opening, attach to the cranium 214, and retain thedevice 110.

To implant the device 110, a craniotomy is performed in the parietalbone 210 anterior to the lambdoidal suture 212 to define an opening 218slightly larger than the device 110. The ferrule 216 is inserted intothe opening 218 and affixed to the cranium 214, ensuring a tight andsecure fit. The device 110 is then inserted into and affixed to theferrule 216.

As shown in FIG. 2, the device 110 includes a lead connector 220 adaptedto receive one or more electrical leads, such as a first lead 222. Thelead connector 220 acts to physically secure the lead 222 to the device110, and facilitates electrical connection between a conductor in thelead 222 coupling an electrode to circuitry within the device 110. Thelead connector 220 accomplishes this in a substantially fluid-tightenvironment with biocompatible materials.

The lead 222, as illustrated, and other leads for use in a system ormethod according to the invention, is a flexible elongated member havingone or more conductors. As shown, the lead 222 is coupled to the device110 via the lead connector 220, and is generally situated on the outersurface of the cranium 214 (and under the patient's scalp 112),extending between the device 110 and a burr hole 224 or other cranialopening, where the lead 222 enters the cranium 214 and is coupled to adepth electrode (e.g., one of the outputs 412-418 of FIG. 4, in anembodiment in which the outputs are implemented as depth electrodes)implanted in a desired location in the patient's brain. If the length ofthe lead 222 is substantially greater than the distance between thedevice 110 and the burr hole 224, any excess may be urged into a coilconfiguration under the scalp 112. As described in U.S. Pat. No.6,006,124 to Fischell et al., Means and Method for the Placement ofBrain Electrodes, issued Dec. 21, 1999, which is hereby incorporated byreference as though set forth in full herein, the burr hole 224 issealed after implantation to prevent further movement of the lead 222;in an embodiment of the invention, a burr hole cover apparatus isaffixed to the cranium 214 at least partially within the burr hole 224to provide this functionality.

The device 110 includes a durable outer housing 226 fabricated from abiocompatible material. Titanium, which is light, extremely strong, andbiocompatible, is used in analogous devices, such as cardiac pacemakers,and would serve advantageously in this context. As the device 110 isself-contained, the housing 226 encloses a battery and any electroniccircuitry necessary or desirable to provide the functionality describedherein, as well as any other features. As will be described in furtherdetail below, a telemetry coil may be provided outside of the housing226 (and potentially integrated with the lead connector 220) tofacilitate communication between the device 110 and external devices.Other portions of a system according to the invention may also bepositioned outside of the housing 226, as will be described in furtherdetail below.

The neurostimulator configuration described herein and illustrated inFIG. 2 provides several advantages over alternative designs. First, theself-contained nature of the neurostimulator substantially decreases theneed for access to the device 110, allowing the patient to participatein normal life activities. Its small size and intracranial placementcauses a minimum of cosmetic disfigurement. The device 110 will fit inan opening in the patient's cranium, under the patient's scalp, withlittle noticeable protrusion or bulge. The ferrule 216 used forimplantation allows the craniotomy to be performed and fit verifiedwithout the possibility of breaking the device 110, and also providesprotection against the device 110 being pushed into the brain underexternal pressure or impact. A further advantage is that the ferrule 216receives any cranial bone growth, so at explant, the device 110 can bereplaced without removing any bone screws: only the fasteners retainingthe device 110 in the ferrule 216 need to be manipulated.

As stated above, and as illustrated in FIG. 3, a neurostimulatoraccording to the invention operates in conjunction with externalequipment. The implantable neurostimulator device 110 is mostlyautonomous (particularly when performing its usual sensing, detection,and stimulation capabilities), but preferably includes a selectablepart-time wireless link 310 to external equipment such as a programmer312. In the disclosed embodiment of the invention, the wireless link 310is established by moving a wand (or other apparatus) havingcommunication capabilities and coupled to the programmer 312 intocommunication range of the implantable neurostimulator device 110. Theprogrammer 312 can then be used to manually control the operation of thedevice, as well as to transmit information to or receive informationfrom the implantable neurostimulator 110. Several specific capabilitiesand operations performed by the programmer 312 in conjunction with thedevice will be described in further detail below.

The programmer 312 is capable of performing a number of advantageousoperations in connection with the invention. In particular, theprogrammer 312 is able to specify and to set variable parameters in theimplantable neurostimulator device 110 to adapt the function of thedevice to meet the patient's needs, upload or receive data (includingbut not limited to stored EEG waveforms, parameters, or logs of actionstaken) from the implantable neurostimulator device 110 to the programmer312, download or transmit program code and other information from theprogrammer 312 to the implantable neurostimulator 110, or command theimplantable neurostimulator 110 to perform specific actions or changemodes as desired by a user operating the programmer 312. To facilitatethese functions, the programmer 312 is adapted to receive clinicianinput 314 (for example, programming and settings) and provide clinicianoutput 316 (for example, information on the status of theneurostimulator); data is transmitted between the programmer 312 and theimplantable neurostimulator device 110 over the wireless link 310.

The programmer 312 may also be equipped to receive external measurements317 from other equipment, not shown. For example, various items ofhospital equipment in an inpatient setting (such as an EKG monitor, anear-infrared spectroscopy (NIRS) monitor, or other equipment) or otherpersonal equipment handled by the patient (such as a Holter monitor orwearable seizure counter, to give two examples) may also uploadmeasurements 317 to the programmer 312, either in real time orperiodically.

The programmer 312 may be used at a location remote from the implantableneurostimulator 110 if the wireless link 310 is enabled to transmit dataover long distances. For example, the wireless link 310 may beestablished by a short-distance first link between the implantableneurostimulator device 110 and a transceiver, with the transceiverenabled to relay communications over long distances to a remoteprogrammer 312, either wirelessly (for example, over a wireless computernetwork) or via a wired communications link (such as a telephoniccircuit or computer network).

The programmer 312 may also be coupled via a communication link 318 to anetwork 320 such as the Internet. This allows any information uploadedfrom the implantable neurostimulator device 110, as well as any programcode or other information to be downloaded to the implantableneurostimulator device 110, to be stored in a database 322 at one ormore data repository locations (which may include various servers andnetwork-connected programmers like the programmer 312). This would allowa patient (and the patient's physician) to have access to importantdata, including past treatment information and software updates,essentially anywhere in the world where there is a programmer (like theprogrammer 312) and a network connection. Alternatively, the programmer312 may be connected to the database 322 over a transtelephonic link.

In yet another alternative embodiment of the invention, the wirelesslink 310 from the implantable neurostimulator 110 may enable a transferof data from the neurostimulator 110 to the database 322 without anyinvolvement by the programmer 312. In this embodiment, as with others,the wireless link 310 may be established by a short-distance first linkbetween the implantable neurostimulator 110 and a transceiver, with thetransceiver enabled to relay communications over long distances to thedatabase 322, either wirelessly (for example, over a wireless computernetwork) or via a wired communications link (such as transtelephonicallyover a telephonic circuit, or over a computer network).

In the disclosed embodiment, the implantable neurostimulator 110 is alsoadapted to receive communications from an interface device 324,typically controlled by the patient or a caregiver. Accordingly, patientinput 326 from the interface device 324 is transmitted over a wirelesslink to the implantable neurostimulator device 110; such patient input326 may be used to cause the implantable neurostimulator device 110 toswitch modes (on to off and vice versa, for example) or to perform anaction (e.g., store a record of EEG data). Preferably, the interfacedevice 324 is able to communicate with the implantable neurostimulator110 through the communication subsystem 430 (FIG. 4), and possibly inthe same manner as the programmer 312 does. The link may beunidirectional (as with a magnet and GMR sensor as described below),allowing commands to be passed in a single direction from the interfacedevice 324 to the implantable neurostimulator 110, but in an alternativeembodiment of the invention is bi-directional, allowing status and datato be passed back to the interface device 324. Accordingly, theinterface device 324 may be a programmable PDA or other hand-heldcomputing device, such as a Palm®, PocketPC®, or Windows Mobile® device.However, a simple form of interface device 324 may take the form of apermanent magnet, if the communication subsystem 430 is adapted toidentify magnetic fields and interruptions therein as communicationsignals.

In various embodiments of the invention, the interface device 324 mayalso include additional functions. In one embodiment, the interfacedevice 324 may include an alert capability, enabling the neurostimulatordevice 110 to transmit an alert to the interface device 324 to provide awarning or other information to the patient. The interface device 324may also include therapy functions, including but not limited totranscranial magnetic stimulation (TMS) capabilities. Such therapyfunctions may be controlled by the neurostimulator device 110, theinterface device 324 itself, or some other device on the network 320.

The implantable neurostimulator device 110 (FIG. 1) generally interactswith the programmer 312 (FIG. 3) as described below. Data stored in thememory subsystem 526 (FIG. 5) can be retrieved by the patient'sphysician through the wireless communication link 310, which operatesthrough the communication subsystem 430 of the implantableneurostimulator 110. In connection with the invention, a softwareoperating program run by the programmer 312 allows the physician to readout a history of sensed data. This history can include detectedneurological events and EEG, perfusion, or other information frombefore, during, and after each neurological event. The history can alsoinclude specific information relating to the detection of eachneurological event, or summary information and statistics describing thehistory and its trends. The programmer 312 also allows the physician tospecify or alter any programmable parameters of the implantableneurostimulator 110. The software operating program of the programmer312 also includes tools for the analysis and processing of recorded EEGrecords to assist the physician in developing optimized seizuredetection parameters for each specific patient.

In an embodiment of the invention, the programmer 312 is primarily acommercially available PC, laptop computer, or workstation having a CPU,a keyboard, mouse and display, and running a standard operating systemsuch as Microsoft Windows®, Linux®, Unix®, or Apple Mac OS®. It is alsoenvisioned that a dedicated programmer apparatus with a custom softwarepackage (which may or may not use a standard operating system) could bedeveloped. The programmer 312 can also be embodied into a specializedmicrochip, which can reside on a device which is plugged into acomputer, for example, via a USB port.

When running a computer workstation software operating program, theprogrammer 312 can process, store, play back and display the patient'sEEG signals, which were previously stored by the implantableneurostimulator 110 of the implantable neurostimulator system. Theprogrammer 312 can also send the data or produce an alarm warning thatcan be sent, for example, over the Internet or to the pager device of aphysician.

As described in U.S. Pat. No. 6,810,285 to Pless et al. for “SeizureSensing Device and Detection Using an Implantable Device,” issued Oct.26, 2004 (which is hereby incorporated by reference as though set forthin full), the computer workstation software operating program also hasthe capability to stimulate the detection and anticipation ofneurological events such as epileptiform activity or neural correlatesof migraine. With real or fabricated electrographic (or other sensor)data, the workstation operating program can show, given a set ofdetection parameters, whether an event of interest would have beenidentified in the data. Furthermore, the software operating program ofthe present invention has the capability to allow a clinician to createor modify a patient-specific collection of information comprising, inone embodiment, algorithms and algorithm parameters for event detection.

The patient-specific collection of sensed information and subsequentresponsive therapy deliveries, may be encoded into control laws. Byidentifying a condition of the signal related to the disorder, as willoccur when detection includes the generation of one or more of a score,probability, or index, related to a characteristic of the detectedevent, the detection method can indicate a specific parameter of thestimulation signal which is to be varied, or set at a specific value, inthe provision of treatment. In general, some characteristic or conditionof detected activity may vary an output or therapy of the system; thisis accomplished through the control laws. Treatment parameters that areused to determine therapy output according to control laws may be basedupon the brain's response to a previously delivered stimulation signalor may be based upon ongoing activity, unrelated to a stimulationepisode, which is sensed by one or more sensors. Each sensor can beconfigured to sense a particular characteristic indicative of aneurological or psychiatric condition, for example, a decrease inperfusion level that has been shown to be related to seizure initiation.The neural modulation signals of the therapy output can include anycontrol signal that augments, attenuates, or inhibits cellular activityin a manner that normalizes or otherwise alters perfusion levels in adesired manner. In the above example, the neurostimulator will augmentbrain activity to increase perfusion. The neurological control systemcan evaluate the neural response or ongoing neural activity, via sensorfeedback, in relation to the neurological disease state (where abnormalperfusion is defined as the disease state). The effective response totherapy may serve as a guide to the adjustment of stimulation accordingto control laws, which is used in subsequent therapy, where thedetermination of treatment parameters is guided by a positive ornegative outcome of the prior therapy in relation to decreasing thedisease state.

For example, control laws may produce an increased stimulation level inresponse to a sensed signal when the sensed signal indicates decreasedperfusion. This is an example of a proportional control law whichhappens to be inversely related to the sensed parameter. Further,according to the control law program, the stimulation may only beincreased to a certain level before alternative therapy is provided. Thealternative therapy may include changing the stimulation signal ratherthan simply increasing the power of the signal since this did notproduce a desired effect. The alternative therapy may also includestimulation at additional leads with the same control signal, sincestimulation at a particular lead did not provide adequate changes in thesensed data with respect to normalizing the disease state. The values ofparameters which are realized by the control laws can be modified in anautomatic manner. For example, the evaluation of the disease state whichis monitored as therapy progresses can also be monitored as treatmentparameters are automatically varied. The control settings which resultin one or more minimum values in disease state vector can be selected toprovide an improved set of stimulation parameters during subsequenttreatment. The set of disease state vectors which result from differentstimulation parameters can be represented as astimulation-and-disease-state transfer function, where the inputstimulation is charted in relation to the output of the system which issensed by the sensors. One or more (local) maxima of the transferfunction, which can represent maximum increase(s) in blood flow, canthen be selected as the parameters utilized by the control laws usedduring treatment. Accordingly, the invention can be realized as a brainmodulation system which treats disease states by providing a stimulationsignal that has parameters, such as intensity, that may be varied. Thestimulation produced by the control laws can produce excitatory orinhibitory stimulation, or both, at different sites. In order toincrease the stability of both control dictated stimulation and thetransfer function used for evaluating control law parameters, thecontrol laws can utilize averaging and integrating routines which dampenthe rate of stimulation adjustment. This may be important when theoptically sensed signals suffer from low SNR (signal-to-noise) levels,or tend to fluctuate considerably and wherein it is the overall meanincrease or decrease in perfusion level which is related to theprovision of therapy. Additionally, in order to increase the stabilityof providing control stimulation in response to a sensed signal, thecontrol law circuit or control program which provides the feedbackcontrol can utilize operational integrators as well as differentiators(e.g., for slope or variance calculations) within the control law tocreate dampened proportional and integrated signals.

The patient-specific collection of detection algorithms and parametersused for neurological activity detection according to the invention willbe referred to herein as a detection template or patient-specifictemplate. The patient-specific template, in conjunction with otherinformation and parameters generally transferred from the programmer tothe implanted device (such as stimulation parameters, time schedules,and other patient-specific information), make up a set of operationalparameters for the neurostimulator. In the disclosed embodiment of theinvention, the patient-specific template includes information about theparameters needed to identify clusters of events, including the durationof the interval within which these events much occur, as will bedescribed in further detail below.

Following the development of a patient-specific template in theprogrammer 312, the patient-specific template would be downloadedthrough the communications link 310 from the programmer 312 to theimplantable neurostimulator 110.

The patient-specific template is used by the detection subsystem 522 andthe CPU 528 (FIG. 5) of the implantable neurostimulator 110 to detectneural events in the patient's data. The patient-specific templates candetect events, such as epileptiform activity, within the patient's EEG(and other sensed) signals, and can be programmed by a clinician toresult in responsive stimulation of the patient's brain, as well as thestorage of data recorded before and after the detection, facilitatinglater clinician review.

Preferably, the database 322 is adapted to communicate over the network320 with multiple programmers, including the programmer 312 andadditional programmers 328, 330, and 332. It is contemplated thatprogrammers will be located at various medical facilities andphysicians' offices at widely distributed locations. Accordingly, ifmore than one programmer has been used to upload EEG records from apatient's implantable neurostimulator 110, the EEG records will beaggregated via the database 322 and available thereafter to any of theprogrammers connected to the network 320, including the programmer 312.

FIG. 4 depicts a schematic block diagram of a stimulator systemaccording to the invention, including an embodiment of the implantableneurostimulator device 110 comprising a small, self-contained,externally programmable and controlled stimulator that is intracraniallyimplanted.

FIG. 4 is an overall block diagram of the implantable stimulator device110 used to modulate cerebral blood flow according to the invention.Inside the housing of the neurostimulator device 110 are severalsubsystems making up the device. The implantable stimulator device 110is capable of being coupled to a plurality of outputs 412, 414, 416, and418 for various types of stimulation as described herein. In theillustrated embodiment, the coupling is accomplished through aninterface such as a lead connector. The described embodiment is adaptedto be used in an implanted environment to modulate a patient's cerebralperfusion for the treatment of epilepsy or other neurological disorders.

The outputs 412-418, each of which may be configured to provideelectrical, magnetic, chemical, thermal or other types of stimulation tothe patient's body, head, or brain, or are otherwise advantageouslylocated near locations of interest in the patient's brain, whereperfusion is desired to be modulated, or from which other areas of thebrain may be modulated. Each of the outputs 412-418 is functionallycoupled to an output interface 420 (this includes communication withremote stimulation devices that interact with the stimulator).

The therapy subsystem 424, which is coupled to the output interface 420,is capable of applying electrical and various other types of stimulationsignals to tissue through the outputs 412-418. This can be accomplishedin any of a number of different manners. For example, with electricalstimulation, it may be advantageous in some circumstances to providestimulation in the form of a substantially continuous stream of pulses,or on a scheduled basis. It is contemplated that the parameters of thestimulation signal (e.g., frequency, duration, waveform) provided by thetherapy subsystem 424 would be stored in this subsystem, but could alsobe adjusted or specified by other subsystems in the implantable device110, and may be received from external equipment such as the programmer312, as will be described in further detail below.

In accordance with the invention, the therapy subsystem 424 may alsoprovide for other types of stimulation, besides the electricalstimulation described above. In particular, in certain circumstances, itmay be advantageous to provide audio, visual, or tactile signals to thepatient, to provide somatosensory electrical stimulation to locationsother than the brain, or to deliver a drug or other therapeutic agent(either alone or in conjunction with stimulation). The provision ofthese other types of stimulation can occur via the external programmer312.

Also in the implantable neurostimulator device 110 is a CPU 428, whichcan take the form of a microcontroller. The CPU 428 is capable ofcoordinating the actions of the device 110 and providing differenttherapies on different schedules (and at different locations) to theoutputs 412-418 via the output interface 420, all according toprogramming and commands received from the programmer 312 and thepatient interface device 324 (FIG. 3). For example, the CPU 428 may havea library of stimulation programs, evaluation algorithms, control laws,models, and other components that can be selected by the programmer 312.

Also provided in the implantable neurostimulator device 110, and coupledto the CPU 428 is a communication subsystem 430. The communicationsubsystem 430 enables communication between the device 110 and theoutside world, particularly the external programmer 312 and the patientinterface device 324, both of which are described above with referenceto FIG. 3, and are used with the disclosed embodiment to command andprogram the device 110. As set forth above, the disclosed embodiment ofthe communication subsystem 430 includes a telemetry coil (which may besituated outside of the housing of the implantable neurostimulatordevice 110) enabling transmission and reception of signals, to or froman external apparatus, via inductive coupling. Alternative embodimentsof the communication subsystem 430 could use an antenna for an RF linkor an audio transducer for an audio link. Preferably, the communicationsubsystem 430 also includes a GMR (giant magnetoresistive effect) sensorto enable receiving simple signals (namely the placement and removal ofa magnet) from a patient interface device; this capability can be usedto initiate EEG recording as will be described in further detail below.

If the stimulation subsystem 424 includes the audio capability set forthabove, rather than the communication subsystem 430, it may beadvantageous for the communication subsystem 430 to cause the audiosignal to be generated by the stimulation subsystem 424 upon receipt ofan appropriate indication from the patient interface device (e.g., themagnet used to communicate with the GMR sensor of the communicationsubsystem 430), thereby confirming to the patient or caregiver that adesired action will be performed, e.g., that an EEG record will bestored.

Additional subsystems in the implantable neurostimulator device 110 area power supply 432 and a clock supply 434. The power supply 432 suppliesthe voltages and currents necessary for each of the other subsystems.The clock supply 434 supplies substantially all of the other subsystemswith any clock and timing signals necessary for their operation,including a real time clock signal to coordinate programmed andscheduled actions.

FIG. 5 depicts a schematic block diagram of an implantable responsiveneurostimulator system according to the invention. The embodimentillustrated in FIG. 5 includes the capabilities of the programmablestimulator described with reference to FIG. 4, and is capable of actingresponsively asset forth below. As the term is used herein, a responsiveneurostimulator is a device capable of detecting neurological events (orother undesired activity) and delivering therapy in response to thatactivity. Therapy can include electrical stimulation specificallyintended to terminate the undesired activity, treat a neurologicalevent, prevent an unwanted neurological event from occurring, or lessenthe severity or frequency of certain symptoms of a neurologicaldisorder. It will be recognized that various other types of therapy,including especially the modulation of perfusion in and around certainstructures of the brain, may also be delivered.

It should be recognized that the embodiment of the device described andillustrated herein is preferably a responsive neurostimulator fordetecting and treating epilepsy by detecting seizure precursors andpreventing and/or terminating epileptic seizures. It will be recognized,and it is described elsewhere herein, that similar methods and devicesmay be used to detect other types of events and to treat otherneurological disorders as well.

FIG. 5 is an overall block diagram of the implantable neurostimulatordevice 110 used for measurement, detection, and treatment according tothe invention. Inside the housing of the neurostimulator device 110 areseveral subsystems making up the device. The implantable neurostimulatordevice 110 is capable of being coupled to a plurality of probes 512,514, 516, and 518. Each probe may be individually or jointly connectedto the implantable neurostimulator device 110 via one or more leads, ormay communicate remotely with the probe interface when the probes havetheir own power sources and communication telemetry, in order to achievesensing and stimulation. In the illustrated embodiment, the coupling isaccomplished through a lead connector. Although four probes are shown inFIG. 5, it should be recognized that any number is possible, and in theembodiment described in detail herein, eight electrodes on two leads areused. In fact, it is possible to employ an embodiment of the inventionthat uses a single lead with at least two electrodes, or two leads eachwith at least a single electrode (or with a second electrode provided bya conductive exterior portion of the housing in one embodiment),although bipolar sensing between two closely spaced electrodes on a leadis preferred to minimize common mode signals including noise.

Certain capabilities of the system may be realized using amicro-stimulator such as a BION®, which communicates with orincorporates the additional sensing methods and systems described hereinto be responsive to different perfusion states. The system can also berealized by a network of microstimulators which provide sensing and/orstimulation in different regions of the brain and which may communicatewith each other or a programmer 312 via telemetry or via physicalconnections. The coordination of such a network to provide cooperativestimulation using the multiple implanted microstimulators can beachieved by the programmer 312 and also by an implanted controller thatcoordinates the operation of the multiple stimulators.

The probes (for example, electrodes) 512-518 are in contact with thepatient's brain or are otherwise advantageously located to sense signalsor provide electrical stimulation. Each of the probes 512-518 is alsoelectrically coupled to a probe interface 520. Preferably, the probeinterface 520 is capable of selecting each electrode (or other sensor orprobe) as required for sensing and stimulation; accordingly, the probeinterface 520 is coupled to a detection subsystem 522 and a stimulationsubsystem 524 (corresponding to the therapy subsystem 424 in FIG. 4). Inone embodiment, the probes can be partially coated and can performin-vivo voltammetry in order to assess neurotransmitter levels. Inanother embodiment, the stimulation/therapy subsystem may providetherapy and have outputs other than electrical stimulation, as describedbelow. The electrode interface may also provide any other features,capabilities, or aspects, including but not limited to amplification,isolation, and charge-balancing functions, that are required for aproper interface with neurological tissue and not provided by any othersubsystem of the device 110.

The detection subsystem 522 includes and serves primarily as a cerebralblood flow and EEG waveform analyzer; detection is accomplished inconjunction with a central processing unit (CPU) 528. The analysisfunctions are adapted to receive signals from the probes 512-518,through the probe interface 520, and to process those signals toidentify neurological activity indicative of events such as seizures orprecursors to a seizure. One way to implement EEG analysis functionalityis disclosed in detail in U.S. Pat. No. 6,016,449 to Fischell et al. for“System for Treatment of Neurological Disorders,” issued Jan. 18, 2000,incorporated by reference above. Additional inventive methods aredescribed in U.S. Pat. No. 6,810,285 to Pless et al. for “SeizureSensing and Detection Using an Implantable Device,” issued Oct. 26,2004, of which some details will be set forth below (and which is alsoincorporated by reference as though set forth in full). The detectionsubsystem may optionally also contain further sensing and detectioncapabilities, including but not limited to parameters derived from otherphysiological conditions (such as electrophysiological parameters,temperature, blood pressure, oxygen saturation, etc.). In general, priorto analysis, the detection subsystem performs amplification, analog todigital conversion, and multiplexing functions on the signals in thesensing channels received from the probes 512-518.

The therapy subsystem 524 is capable of applying electrical and othertypes of stimulation to neurological tissue through the probes 512-518,to the extent such probes are capable of applying stimulation. This canbe accomplished in any of a number of different manners. For example, itmay be advantageous in some circumstances to provide electrical or otherstimulation in the form of a substantially continuous stream of pulses,or on a scheduled basis. Preferably, therapeutic stimulation is providedin response to abnormal neurological events detected by the EEG analyzerfunction of the detection subsystem 522 and to modulate cerebral bloodflow as described herein. The EEG analyzer function of the detectionsubsystem 522 can utilize modules of the perfusion analyzer subsystem,which identify different conditions related to blood profile includingflow, volume, gas content, and other aspects: this may advantageouslycontextualize activity analyzed by the EEG analyzer. The output of thedetection subsystem can be fed to control laws in order to provide thestimulation signal. As illustrated in FIG. 5, the therapy subsystem 524and the analysis functions of the detection subsystem 522 are incommunication; this facilitates the ability of the therapy subsystem 524to provide responsive stimulation as well as an ability of the detectionsubsystem 522 to blank the amplifiers while electrical stimulation isbeing performed to minimize stimulation artifacts. It is contemplatedthat the parameters of the stimulation signal (e.g., frequency,duration, waveform) provided by the therapy subsystem 524 would bespecified by other subsystems in the implantable device 110 (forexample, waveforms stored in the memory subsystem 526), as will bedescribed in further detail below.

In accordance with the invention, the therapy subsystem 524 may alsoprovide for other types of stimulation, besides the electricalstimulation described above. Such stimulation may be provided throughthe probes 512-518, or alternative therapy outputs may be provided, suchas a thermal stimulator 536, a drug dispenser 538, or an audio orelectromechanical transducer 540, which may be adapted for placement in,on, or near the brain, or elsewhere. The transducer 540 can providetactile stimulation or pressure according to a signal, to areas of thebrain or body; it has been observed that physical pressure can changeneuronal activity. Selective amounts of focal pressure may be found toprovide modulation of activity in a desired fashion. Cells are sensitiveto mechanical stimuli, and actively respond through a variety ofbiological functions including migration, morphological changes, andalterations in gene expression and protein synthesis. Cell-distinctfunction (e.g., growth) or dysfunctional phenotypes (e.g.,atherosclerosis and asthma) involve such mechanisms in response tospecific biomechanical stimuli. To understand the cellular response tomechanical stress, numerous experiments have been conducted to apply aquantified mechanical stimulus to a single cell, and study its response.See, e.g., Tavalin S J et al., Mechanical Perturbation of CulturedCortical Neurons Reveals a Stretch-Induced Delayed Depolarization, J.Neurophysiol. 1995. In particular, in certain circumstances, it may beadvantageous to provide audio, visual or tactile signals to the patient,to provide somatosensory electrical stimulation to locations other thanthe brain, or to deliver a drug or other therapeutic agent (either aloneor in conjunction with stimulation).

Also in the implantable neurostimulator device 110 is a memory subsystem526 and the CPU 528, which can take the form of a microcontroller. Thememory subsystem is coupled to the detection subsystem 522 (e.g., forreceiving and storing data representative of sensed EEG signals andevoked responses), the therapy subsystem 524 (e.g., for providingstimulation waveform parameters to the therapy subsystem), and the CPU528, which can control the operation of (and store and retrieve datafrom) the memory subsystem 526. In addition to the memory subsystem 526,the CPU 528 is also connected to the detection subsystem 522 and thetherapy subsystem 524 for direct control of those subsystems.

Also provided in the implantable neurostimulator device 110, and coupledto the memory subsystem 526 and the CPU 528, is a communicationsubsystem 530 (corresponding to the communication subsystem 430 of FIG.4). The communication subsystem 530 enables communication between thedevice 110 and the outside world, particularly the external programmer312 and patient interface device 324, both of which are described abovewith reference to FIG. 3. As set forth above, the disclosed embodimentof the communication subsystem 530 includes a telemetry coil (which maybe situated outside of the housing of the implantable neurostimulatordevice 110) enabling transmission and reception of signals, to or froman external apparatus, via inductive coupling.

The subsystems 524 and 530, and the power supply 532 and clock supply534 provide the same benefits as corresponding components describedearlier for FIG. 4.

It should be observed that while the memory subsystem 526 is illustratedin FIG. 5 as a separate functional subsystem, the other subsystems mayalso require various amounts of memory to perform the functionsdescribed above and others. Furthermore, while the implantableneurostimulator device 110 is preferably a single physical unit (i.e., acontrol module) contained within a single implantable physicalenclosure, namely the housing described above, other embodiments of theinvention might be configured differently. The neurostimulator 110 maybe provided as an external unit not adapted for implantation, or it maycomprise a plurality of spatially separate units each performing asubset of the capabilities described above, some or all of which mightbe external devices not suitable for implantation. Also, it should benoted that the various functions and capabilities of the subsystemsdescribed above may be performed by electronic hardware, computersoftware (or firmware), or a combination thereof. The division of workbetween the CPU 528 and the other functional subsystems may also vary:the functional distinctions illustrated in FIG. 5 may not reflect thepartitioning and integration of functions in a real world system ormethod according to the invention.

FIG. 6 illustrates details of one embodiment of the detection subsystem522 (FIG. 5). Inputs from the probes 512-518 are on the left, andconnections to other subsystems are on the right. The probes can besensors which sense electrical patterns (e.g., electrodes), temperature,characteristics of blood, electrocardiogram, movement, posture, andother characteristics related to the patient or to the patient'sactivity, as are described elsewhere herein.

Signals received from the probes 512-518 (as routed through the probeinterface 520) are received in an input selector 610. The input selector610 allows the device to select which probes (for example, selected fromthe probes 512-518 of FIG. 5; it should be noted that the input selector610 has eight inputs as illustrated) should be routed to whichindividual sensing channels of the detection subsystem 522, based oncommands received through a control interface 618 from the memorysubsystem 526 or the CPU 528 (FIG. 5). Preferably, for electrographicand impedance measurements, each sensing channel of the detectionsubsystem 522 receives a bipolar signal representative of the differencein electrical potential between two selectable electrodes. Accordingly,the input selector 610 provides signals corresponding to each pair ofselected electrodes (of the probes 512-518) to a sensing front end 612,which performs amplification, analog to digital conversion, andmultiplexing functions on the signals in the sensing channels.

A multiplexed input signal representative of all active sensing channelsis then fed from the sensing front end 612 to a waveform analyzer 614.The waveform analyzer 614 is preferably a special purpose digital signalprocessor (DSP) adapted for use with the invention, or in an alternativeembodiment, may comprise a programmable general purpose DSP. Thewaveform analyzer 614 contains modules for analyzing sensed data, suchas an EEG analyzer function, a perfusion analyzer function, and atemperature analyzer function; these functions may be implemented in thesame DSP with different programming, or may be implemented separately.In the disclosed embodiment, the waveform analyzer has its ownscratchpad memory area 616 used for local storage of data and programvariables when the signal processing is being performed. The signalprocessor performs suitable processing, measurement, and detectionmethods as described generally above and in greater detail below. Anyresults from such methods, as well as any digitized signals intended forstorage transmission to external equipment, are passed to various othersubsystems of the neurostimulator device 110, including the memorysubsystem 526 and the CPU 528 (FIG. 5) through a data interface 620.Similarly, the control interface 618 allows the waveform analyzer 614and the input selector 610 to be in communication with the CPU 528. Thewaveform analyzer can also combine information across sensors toevaluate data, detect events, and produce its results, and canaccomplish pattern matching based upon templates and algorithms, applycontrol laws to create stimulation therapy, generate scores,probabilities, and indexes which reflect conditions of the sensedsignals and guide the stimulation treatment.

The evaluation of the sensed signal, the evaluation of a reference valueor criterion to which the sensed signal will be compared, or thecomparison itself can be achieved by means of one or more of thefollowing: a model, an algorithm; an equation; a transform (such asHilbert, Fourier, or wavelet method); filtering; temporal analysis ortime-frequency analysis which can be combined with spatial analysis;parametric and non-parametric statistics; multivariate and clusteranalysis, including assessment by discriminant analysis or computationof Mahalnobis or Euclidean distance; factor or independent componentanalysis; phase or latency analysis; correlation/regression analysis;non-linear; fractal, and fuzzy logic analysis techniques and measures ofchaos, complexity or entropy including Lyapunov exponents andKolmogorov-Sinai. There are numerous other possibilities. The sensedsignal can be related to an event, the time before or after an event,and can be a signal sensed in response to stimulation, can be signalssensed both before and after stimulation. The examples of spectralanalysis, filtering, and component analysis given above may be relatedto the detection of the optical signal and the detection of patternswithin the optical signal (and separating the signal from noise),however, wavelet or other time-frequency analysis can also be utilizedin order to generate a spectrogram which may be analyzed in order todetect or remove periodicities within the sensed data. For example,fluctuations in the perfusion data related to heart rate can be removed,or compensated for, prior to evaluating the changes in the perfusionwhich occur within a sensed brain area. In any case, when evaluating thesensed optical data and comparing this to a referenced data set, someestimate of perfusion increase or decrease will be needed in order toguide the control law in providing treatment. For example, if aninferential statistic such as re-sampling (e.g., bootstrap) analysis isprovided, then the histogram data can be divided into deciles (or othercumulative density function may be used). If a comparison of an estimateof the current sensed data with this reference dataset indicates thatthe current data is below some criteria (e.g., within the lower 2deciles) then stimulation can be initiated and the magnitude of thestimulation can be proportionate to the results of the comparison.Alternatively, therapy may not be graded by degree of the sensed dataand the therapy may simply be responsive to the detection of an event.For example, if optical data sensed at multiple leads is submitted to amultivariate equation, and the resulting score indicates that theprobability of a disease state is at least 80%, then this can result instimulation, regardless of the size of features which may exist in thesensed data. The multivariate equation may be a discriminant functionwhich was previously derived using discriminant analysis on a trainingset of data which included data for which a medical professionaldetermined a disease state existed, and data which was regarded by themedical professional as not being related to a disease state. Whensensed data occurs across multiple modalities such as both optical andelectrical, these measures can be normalized for the subject andcombined into a disease state vector, which may be conceptualized andevaluated, as a Mahalanobis distance from an origin which is a desiredtreatment site. Accordingly, when the disease state vector increases insize then some parameter may be automatically increased or stimulationmay be triggered in an attempt to decrease the size of this vector.

The sensed signal can be used to provide stimulation according to, forexample, one or more models; algorithms; subroutines; equations; controllaws, which may be rule-based and accomplished in series or in parallel,be guided by fuzzy logic, be guided by linear or non-linear rule sets,be guided according to a transfer, step, or other function; the resultof a comparison of sensed data to reference data or threshold; a score,probability, or index; and the sensed data can be used to determine how,when, where, and what stimulation subsequently takes place. These rules,which would generally (but not necessarily) be computed offline, can becodified into one or more control laws for use in the implantableneurostimulator 110.

FIG. 7 illustrates the components functionally present in an exemplarytherapy subsystem 524 according to the invention. Through an outputselector 710, the therapy subsystem 524 is capable of driving a numberof outputs, including the thermal stimulator 536, the drug dispenser538, and the audio transducer 540 illustrated in FIG. 5. Other outputsinclude leads for electrical stimulation and other stimulators asdescribed in greater detail below with reference to FIGS. 8-11 and 13.Preferably, the output selector 710 is configured and may be programmedto drive more than one output, either in sequence or simultaneously.

The nature of the outputs is defined by a signal generator 712,advantageously designed to be able to produce different types of outputsignals for different types of outputs. For example, for electricalstimulation, biphasic pulsatile stimulation or low-frequency sine wavestimulation may be advantageous signals, whereas for a burst of thermalstimulation, a single-polarity longer-duration pulse signal may be moreappropriate. Thermal stimulation can be provided using a heating elementsuch as a resistor configured to be used with the electrical stimulationcontacts. Alternatively, cooling may be desirable. When treatingepilepsy by cooling, the cortical surface should not usually be cooledto lower than 20° C., but should be cooled to lower 26° C. for anappreciable anti-epileptic effect to be gained. Small thermoelectriccooling devices, called Peltier devices, can be used to provide cooling.Cooling may be a particularly advantageous procedure when the epilepsyfocus is in a language or primary motor area, since tissue stimulation,ablation, or resection may provoke disorders in behaviors controlled bythese areas. For various forms of active sensing described in detailbelow (in which a physiological or other physical response to an appliedstimulus is measured), signals generated by the signal generator 712 arepreferably coordinated with measurements made by the detection subsystem522 (FIG. 5).

Such coordination and control of the signal generator 712 isaccomplished through a therapy controller 714, which may include memory716 to “play back” therapy waveforms, to store parameters used to createwaveforms, and for other purposes—such waveforms may also be receivedvia a data interface 720 from the main memory subsystem 526 or the CPU528. The therapy controller receives input from a control interface 718,which is coupled to the CPU 528, thereby allowing the CPU 528 to controlboth the therapy subsystem 524 and the detection subsystem 522. Throughthe control interface 718, the CPU 528 is also capable of controllingthe application of therapy (or other stimulation) to a desiredcombination of outputs via the output selector 710.

FIGS. 8-13 illustrate several embodiments of probes advantageouslyusable in a system according to the invention to measure and modulateperfusion. The chronically implantable probes illustrated in FIGS. 8-13are advantageously connected to a device 110 according to the invention,and in the illustrated embodiments, have distal ends generally 0.5-3 mmin diameter, are at least partially flexible, and are of a lengthsufficient to reach from the device 110 to a desired target. Theillustrations are schematic in nature and are not to scale. The probesof FIGS. 8-13 are illustrated as generally cylindrical depth probes,capable of being positioned within the gray or white matter of apatient's brain, but it should be recognized that surface corticalprobes are also advantageous in certain embodiments; the differencesbetween the illustrated probes and their cortical counterparts would beknown to a practitioner of ordinary skill, and would primarily entail adifferent (paddle-shaped) physical configuration at the distal end.

Referring now to FIG. 8, an optical probe 810 capable of measuringcerebral perfusion and applying optical stimulation is illustrated. Theprobe 810 includes an optically translucent distal tip 812 and opaquebarrier 814 separating a light source 816 (typically one or more lightemitting diodes, or LEDs) and a light sensor 818 (typically aphotodiode, but it may also include a CCD or other light sensor). In theillustrated embodiment, the light source 816 and light sensor 818 areconnected to a buffer 820, which in turn is coupled to the device 110.This configuration allows a single set of control wires (typically apair) to both send information bi-directionally between the probe 810and sensor 818; in this embodiment the probe interface 520 (FIG. 5)would perform the buffering functions otherwise provided by the buffer820.

The optical probe 810 of FIG. 8 is advantageously used to measureperfusion via pulse oximetry methods. The disclosed embodiment isconfigured to measure reflected light; embodiments measuringtransmissivity are also possible. The light source 816 includes twoLEDs, for estimating both oxyhemoglobin HbO₂ and deoxyhemoglobin (HbR).For example, one red LED in the 600-750 nm range and an infrared LED inthe 850-1000 nm range may be used, or in any case the wavelengths chosenare advantageously below and above approximately 805 nm, at which pointthe two chromophores are similarly absorbed (this is the hemoglobinisobestic point). To obtain a single measurement, the two LEDs arepulsed (preferably in sequence) and two corresponding measurements areobtained at the light sensor 818, which may be a photodiode. The lightsensor 818 can be turned to a specific wavelength, or spectral analysismay be used to derive energy at a specified frequency, or, rather thanperforming spectral analysis, lock-in amplifiers can be used to obtaindata for specific frequencies in the near-infrared spectrum. The ratioof red reflectivity to infrared reflectivity is calculated (by thedetection subsystem 522 or the CPU 528). Preferably, multiple ratiomeasurements are obtained over the course of at least one heart beat toobtain a value for peak perfusion, typically be subtracting minimumvalues (baselines) from maximum values (maximum perfusion). The peakvalue is compared to a preprogrammed lookup table to obtain an oxygensaturation value; the contents of the lookup table would be routing tocalculate for a practitioner of ordinary skill. It should be noted thatdifferent methods of near infrared spectroscopy (NIRS) techniques may beimplemented as well, and may combine and utilize several differentperfusion measures.

It will be noted that perfusion measurements obtained by the opticalprobe 810 are typically relevant only in comparison to previouslyobtained values of trends, as measurements may be affected over a longterm by tissue growth and other physiological changes around the probe810. As will be described in details below, systems and methodsaccording to the invention use trends accordingly.

In an embodiment of the invention, the light source 816 is furtheroperable to optically stimulate brain tissue, which may result inperfusion changes or other desired neurophysiological results. Forpurposes of measurement, however, it is preferable to operate the lightsource 816 with low amplitude, duration and other characteristics thatare unlikely to cause undesired effects.

The optical probes may be placed in a number of different locations. Theprobes can be placed on the scalp, as can occur when an external devicewill communicate with implanted components of the system. Thiscommunication can occur using the programmer 312 which receivesinformation from the external probes and sends this information to theimplanted device 110. If sensors are located on the outside of theskill, MR image data can be used to derive a model (e.g., of the bone,brain, cerebrospinal fluid and muscle tissues), which accounts fortransfer characteristics of intervening tissue, and which can beincorporated into an analysis of the optical data. An iterative-basedmethod for improving localization in diffuse tomography reconstructionmay be used, which is based upon the MRI data. Alternatively, and withsome benefit, the probes are implanted in the patient and positioned onthe dura, cortex, or in sub-cortical locations and structures. Theprobes can also be placed to sense from the arterial and venous passagesof a region as may occur in order to determine the transfer function ofoxygen utilization in a region of tissue.

Assessment of a disorder such as epilepsy, with respect to both sensingperfusion irregularities and also determination of probe placement, canbe assisted by various imaging procedures. Regional Perfusion Imaging(RPI) is an MRI procedure that matches cerebral arteries to flowterritories. RPI is designed to non-invasively provide standardperfusion and cerebral blood flow data, and determine the contributionof each artery as well as the role of collateral vessels. RPI isvaluable in determining the etiology of cerebral ischemia with respectto a disorder, in identifying the supply vessels of capillaryabnormalities and arteriovenous malformations, and in assessing thecollateral flow in the case of stenosis. While many conventional methods(e.g., contrast-enhanced angiography) for visualizing the vascular treesthat terminate from major cerebral arteries, and for assessingcollateral flow, can also be used, these techniques are often invasive.Unlike RPI, these other methods do not provide comprehensive informationabout tissue perfusion. By placing the sensors on the relevant cerebralarteries and/or cerebral and cerebellar veins, as determined by RPItechniques, the functional perfusion of an area may be assessed in animproved manner. Of course, RPI can also be used to guide placement ofstimulation devices when these are different from the probes, in orderto provide improved therapy.

Several assumptions are often made in measures of CBF obtained usingNIRS. For example, it may be assumed that cerebral metabolic rate, bloodflow and/or volume remain constant during the short measurementinterval. This may not be true, and further, many other factors produceconsiderable variation in the measurements. In order to increase thevalidity of the measurements, NIRS sensing and event detection can belimited to, or adjusted for, the patient's position, posture (e.g.,supine), activity level, or other sensed characteristic, or even can beimplemented only during certain times of day (e.g, when the patient issleeping). The sensitivity to brain activation and oxygen levels, ormore precisely, relative changes in brain activation, is oftencontaminated by several signals such as systemic physiological signals,which can account for a larger percent signal variation than that of thebrain activation. In some cases, it has been observed that these othersignals may even phase-lock with the stimulation, causing the opticalsignal measured centrally to detect changes related to both central andperipheral responses to stimuli.

Accordingly, NIRS data can be combined with, or measured in relation to,pulse oximetry, such as only measuring NIRS data at the peak of the EKG.Further, central NIRS data can be measured in the context of othermeasurement of arterial oxygen saturation (SaO₂), or other arterial gasestimations, measurements of transcutaneous oxygen and carbon dioxide,measures of systemic circulation as monitored by electrocardiograph andinvasive or non-invasive blood monitors (e.g., blood pressure sensor, orflowmetry), in order to obtain a measurement of peripheral changes whichcan affect central NIRS readings. In other words NIRS data, and changes,can be evaluated relative to peripheral changes in order to provide moreaccurate sensing and decrease false alarms. For example, if a change inan NIRS measure occurs at a probe monitoring the brain, at a time closeto a peripheral change in the cardiovascular measurements (factoring in,when appropriate, delays between the two sites), then such a change maybe ignored, whereas in the absence of this change, the NIRS measure mayindicate a cerebral event for which responsive neurostimulator isappropriate.

The invention can utilize circulation monitoring of both central andperipheral regions to permit measurement or inference of the generalperfusion of the monitored tissue, in relation to manifestation orpromotion of different neural disorders. Methods can include NIRS,various types of flowmetry, ultrasound velocity, and use of anelectromagnetic or magnetic flowmeter in the measurement of voltageinduced in a moving electroconductive liquid as it crosses the lines ofa magnetic field, since this is directly proportional to the flow rate.

Recapitulating to some extent, then, an NIRS signal is analyzed relativeto a cardiopulmonary event, such as a component of the EKG signal, or aperipheral measure such as instantaneous blood pressure or heart rate.Statistical and signal analysis procedures such as template matching andcan be used to classify, score, or otherwise analyze the optical data.For example, the NIRS signal, or a transform of the NIRS signal, such asa frequency transform, can be analyzed over time using a principlecomponent analysis (PCA) or an independent component analysis (ICA) todetermine the principle spatial components of the spatial-temporalcovariance of baseline NIRS data. This can then be used to filtersystemic or evoked signal variation from subsequent brain NIRSactivation data. In an embodiment, data from implantable sensors iscollected for this analysis at least in part by the implantableneurostimulator device 110, which later transfers the data to theprogrammer 312 for combination with other data (e.g., data from anon-invasive NIRS unit) and for offline analysis. This approach isparticularly useful to collect baseline data in an inpatient environmentor on a time-limited outpatient basis. Further, temporal orspatiotemporal (or frequency and phase for frequency transformed data)PCA can also be used to analyze and classify the incoming signalsrelative to a baseline period, or a period that is indicative or asystem of the disorder to be treated (e.g., during a seizure in the caseof epilepsy). Additionally, post-processing of time series data taken bythe NIRS can include analysis procedures which utilize multiple steps,each relating to the time or frequency domain. For example, clusteringalgorithms can assist in classification or segmentation of data, usinglinear or non-linear analysis, including fuzzy-logic schemes, applied tothe time, time-frequency (e.g., wavelet outputs), or spectral data. Poststimulation data can also be assessed using these methods. For example,a level of excitation of brain tissue can be estimated by examining thehemodynamic response to a brief period of therapeutic stimulationcompared to the perfusion profile prior to the stimulation. This can beused in a system according to the invention to assess therapeuticefficacy on an off-line basis using the programmer 312 or the database320, thereby allowing the neurostimulator device 110 to be programmedwith the most effective treatment regimen.

In embodiments of the invention, various useful measures and indices canbe computed using NIRS. Regional cerebral oxygen saturation may beassessed by a tissue oxygen index (TOI). Brain absorption of the lightsignal is due to the main cerebral chromophores, which are oxyhemoglobin(HbO₂) deoxyhemoglobin (HbR), and oxidized cytochrome oxidase (CtOx). Ithas been shown that the HbO₂ and HbR measures are related directly tocellular activation. Increases in cerebral blood volume (CBV) tend tocorrelate with increases in HbO₂ and in HbR, which sum to equal Total Hb(or Hb_(total) or Hb_(T)). These measurements are normally relativemeasurements with an arbitrary zero point, and the change is related tochanges in CBV.

The conditions of the sensed NIRS signal can refer to thecharacteristics of the signal related to changes in these measures. TheHbO₂ and HbR measurements can be assessed independently, or can be usedin an index combining these measures in various useful ways. Forexample, HbO₂ and HbR measurements can be measured alone, or HbO₂+HbRcan be assessed to provide Hb_(T), or HbO₂/(HbO₂+HbR) can reflectrelative oxygen utilization as a function of blood flow. Hbdiff([HbO₂−HbR]) is often used to track changes attributable to saturationalone. Small changes in HbO₂ concentration can be reflective of cerebralblood flow, remembering that the accumulation of HbO₂ in the brain isdependent on both arterial inflow and venous outflow. Regional cerebraloxygen saturation (rSO₂), may be derived from the ratio of HbO₂ to totalhemoglobin Hb_(T), which is a percentage value of rSO₂. NIRS methods caninclude diffuse optical imaging (DOI) techniques including diffuseoptical tomography (DOT). Each sensor may have a source, or severalsensors can absorb light from a relatively distal source, the amountabsorbed being related to activation of the regions between the sourceand sensor.

While two wavelengths are often used to accomplish NIRS, additionalwavelengths can also be relied upon. For example, the NIRO 300(Hamamatsu Photonics KK, Hamamatsu, Japan) uses four wavelengths ofnear-infrared light (775, 825, 850, and 904 nm). The NIRO 300 sensorcontains a laser diode and three detectors placed at 4 or 5 cm from thesource of emitting light. Its TOI (%) measure is based upon the ratio ofHbO₂ to Hb_(T). Previous models of the NIRO only monitored changes inHbR concentration and the redox state of cytochrome oxidase with amodified Beer-Lambert Equation. The current NIRO also improves itsmeasurements using a specially resolved spectrometer (SRS), whichcombines multidistance measurements of optical attenuation in order toestimate the absolute concentration of HbO₂ and HbR in the tissue,rather than relative concentrations. This is possible since the valuesderived by STS are not differentially altered by influences ofdiffusion. As per this variant of NIRS, the NIRS source can be generatedcontinuously, can be modulated (e.g., pulsed), can be transmitted insequential pulses, and can be responsively generated under certainconditions or at certain times. It will be recognized that while onlycertain spectral components and wavelengths are currently used for boththe optical source and measurement, the invention can be expanded toother wavelengths that have been found to be useful in determining aperfusion profile. In an embodiment of the invention, measurements froma NIRO 300 or similar tool may be provided as external measurements 317to the programmer 312, and used in combination with measurements fromthe implantable neurostimulator device 110 of the invention (includingelectrographic and optical measurements, to name two possibilities) toassess a patient's perfusion in areas of interest, either in baselinestates or in an episode of epilepsy or other neurological disorder.

Accordingly, NIRS can provide both relative and absolute measures for anumber of perfusion related attributes. While changes in measures arecurrently relied upon more frequently than absolute measures, with theadvances in technology absolute measures are becoming more accurate, andadditionally using implanted sensors rather than sensors attached to thescalp should increase the accuracy of measurement. The sensed signalobtained at one or more probes can be compared, for example, by beingz-transformed, to either self or population normative data, or to both.Signal processing techniques can extract relevant features from the NIRSdata and can compare these to templates, use these in control laws,submit these to algorithms, statistically compare normative data, orsimply compare these to a threshold. The measured data can then be usedto produce time series data, which can be analyzed using both temporaland spectral techniques which are able to identify conditions of thesignal and provide event detection.

The analysis of the time series data can include assessment of temporal,spatial, and spatiotemporal patterns of activity as detected acrossmultiple sensors. The signals can be assessed using techniques which arecommonly applied to the analysis of biological data, including theslower responses of the Galvanic skin response, like the orientingresponse, which have similar durations to some of the hemodynamicresponses measured in NIRS (e.g., from 2-6 seconds). For example, thearea under the curve, rate of ascent, rate of descent, the duration oramplitude of the half-maximum value, for a measure such as HbO₂ level,can be assessed. When HbO₂ and HbR are both assessed, the differencebetween the two curves can be calculated. Because NIRS is able tomeasure hemodynamic, metabolic, and fast neuronal responses to brainactivation, the analysis techniques chosen will depend on the biologicalprocess that is being assessed. The shortest available sampling time ofone-half second in commercially available NIRS equipment has recentlybeen shortened to ⅙ of a second, allowing observations of more rapidlychanging phenomena. For example, changes in HbO₂ data may contain aheart beat component superposed upon signals which slowly change overtime. Measurement of these slow components can be accomplished afterfiltering out the fast component(s), and measurement of the fastcomponent(s) can be made by transforming the data into the frequencydomain and then measuring the spectral power of the fast frequency(ies).A high frequency sampling rate permits NIRS to be effective fordetecting physiological responses, transient changes activity, andactivity which may be related to events such as external stimulation ormanipulation. The lower speed sampling may have other advantages such asbeing characterized by lower noise levels. The sampling rate may bespecified according to the purpose of the measurement.

An index of synchronization between different brain regions may also beused in the analysis of data such as NIRS data. It is not only importantto identify the neural populations underlying the neural event but alsoto depict their temporal dynamics. This can be accomplished usingvarious non-linear and linear methods of analysis and correlationanalysis. For example, using a geometric method, a phase portrait can bederived to obtain a functional may of neural changes in oxygensaturation as measured by NIRS. A phase portrait can be generated bytaking the signal of one location as a reference for the other locationslike a Lissajous figure. Measuring synchronization using the shape of anellipse in phase portrait has the advantage for physiological data thatit can reflect neural dynamics in both space and time. Synchronizationcan also be examined using linear estimates of synchronization wherethese can be indexed by the deviation of the actual distribution of thephases from a uniform distribution, or the relative phases, in the casewhere the phases of components of two sensors are compared.

NIRS has certain advantages compared to other sensing modalities. Forexample, spatially-resolved NIRS can provide better localizationcapabilities than EEG, especially when sensed from the scalp, and canrequire less processing of the data in order to obtain thislocalization. Sensing of NIRS data can occur during the stimulationperiod since it is not subject to electrical artifact, as would besensed EEG data. While Hb_(T) provides a measure of the cerebral bloodvolume (CBV), the individual concentrations of the two forms ofhemoglobin are determined by physiological characteristics such asregional blood volume, atrial/venous blood flow, and metabolic rate ofoxygen consumption, which is related to cellular activity.

NIRS can be used not only to identify regions of activation, but alsodistributed networks within which types of activation, such as seizure,can occur. By using two or more sensors, located at different regions ofa neural network, the relative activation of that network can bedetermined. Seizures do not simply propagate omnidirectionally, but arenormally distributed across neural tissue that is functionallyconnected. NIRS data can assist to determine the most likely path of aseizure through the network and can therefore assist in determiningwhere stimulation should take place, as well as evaluating the effectsof the stimulation. NIRS data can also be used to categorize a type ofneural event, such as permitting classification of seizure type, wheredifferent seizure types have been found to product different, sometimeopposite, changes in NIRS measurements.

A thermal probe 910 is illustrated in FIG. 9; it is capable of measuringtemperature. In one embodiment, cerebral perfusion can be measured bythermographic means. The thermal probe 910 includes a thermallyconductive distal tip 912 (the shape of which is as desired to reach apreferred target or region) coupled to a thermal energy source 914 (suchas a Peltier junction or stack) and a temperature sensor 916 (in oneembodiment, a temperature sensitive resistor). The thermal probe 910 isotherwise relatively thermally insulated. As shown the thermal energysource 914 and the temperature sensor 916 are electrically coupled to aswitch 918 facilitating the use of a single set of control wires, and aswith the optical probe 810, the switch 918 may be omitted in favor ofmultiple connections. The switch 918 need not be as complex and thebuffer 820 (FIG. 8), as thermography calls for temperature measurementsto be obtained after thermal stimulation is applied; simultaneousoperation of the thermal energy source 914 and the temperature sensor916 is generally not required. The switch is advantageously operated viasignals from the device 110.

Thermographic measurement of perfusion is generally accomplished byapplying a caloric stimulus (via the thermal energy source 914), eitherhot or cold, and measuring the temperature over an interval thereafterto determine how quickly heat dissipates. Increased dissipationcorrelates with higher blood flow. Thermographic techniques, and theircalibration, are well known to practitioners of ordinary skill. As withoptical measurements, thermographic measurements of perfusion are mostuseful in a relative sense, compared to a previously measured baseline,and may be subject to long term changes.

Thermal stimulation may also be performed by the probe 910 to modulatecerebral perfusion; generally, an increase in temperature will tend toincrease blood flow in the region, and a decrease in temperature willlead to lower blood flow. Preferably, when measurements are to be made,smaller perturbances to temperature are preferred. Thermographic probesas generally described herein are commercially available.

FIG. 10 illustrates a sonic probe 1010, which can include an ultrasonictransmitter 1012, an ultrasonic receiver 1014, and a processor 1016 allbehind a partially acoustically transparent distal probe tip 1018. Inthe disclosed embodiment, the ultrasonic probe 1010 is adapted tomeasure perfusion via flowmetry (e.g., laser or ultrasound Dopplerflowmetry), a technique well known in the art. The disclosed embodimentincludes the Doppler processing in the probe via the processor 1016,though the calculations may also be performed on board the device 110.

The ultrasonic transmitter 1012 is, in the disclosed embodiment, apiezoelectric transducer configured to operate at a frequency greaterthan approximately 1 MHz. The ultrasonic receiver 1014 is adapted toreceive at a range of similar and compatible frequencies. Pulsedmeasurements enable selection of measurement depth (e.g., the distancein front of the probe 1010 from which a measurement is taken), but in apresently preferred embodiment of the invention, measurements are takenin near proximity to the sensor.

Sonic stimulation may also be performed, for example using an ultrasonicprobe 1010 according to the invention; ultrasonic stimulation generallyoperates to increase perfusion at the stimulation site. Differentpatterns of periodic, continuous, or responsive sonic stimulation may beused to cause different changes in perfusion, for example, stimulationof contralateral structures may decrease perfusion at an intendedipsilateral (to sensor) site.

Ultrasonic flow probes potentially suitable for use in connection withvarious embodiments of the present invention are commercially available.Regardless of the embodiment, when placing an ultrasonic probe, it isparticularly important to avoid air bubbles and other gas pockets infront of the transducer, as such obstructions may confound measurements.

When used with the stimulator of FIG. 4, the probes described herein,such as those shown in FIGS. 6-13, can serve merely as stimulationdevices without providing sensing.

FIG. 11 illustrates an electromagnetic probe 1110 according to theinvention, which includes a first field generating coil 1112 and asecond sensing coil 1114 behind a magnetically permeable tip 1116. Aswith the other probe embodiments, a buffer 1118 is provided to enable asingle set of control wires to be used and to offload some processingfrom the device 110.

The electromagnetic probe 1110 is capable of measuring blood flow volumeand rate by applying a magnetic field with the first field generatingcoil 1112 and measuring changes in electrical potential created acrossthe second sensing coil 1114 caused by the movement of ferromagnetic orpolarized objects, in the present case blood cells, within the field.The general technique of flowmetry, such as electromagnetic flowmetry,is well known.

Localized electromagnetic stimulation may also be applied by theelectromagnetic probe 1110. Depolarization potentially caused by amagnetic field may have therapeutic effects at or near a seizure focusor at a functionally relevant brain structure, or the magnetic field maybe manipulated to affect perfusion in a desired manner according to theinvention. In an embodiment, transcranial magnetic stimulation may beapplied at a global scale (e.g., through the interface device 324, FIG.3) to accomplish similar results.

FIG. 12 illustrates an electrochemical oxygen probe 1210, which includesan oxygen sensor 1212 disposed behind a permeable tip 1214 or membrane.There are three common types of dissolved oxygen sensing probes:polarographic sensors, galvanic sensors, and optical fluorescencesensors, any of which may be adapted to serve the purposes of theinvention to the extent they are biocompatible for long term implantpurposes. Dissolved oxygen levels correlate positively with perfusionlevels, and may be used by systems and methods according to theinvention to measure blood flow and gas composition. The disclosedoxygen probe 1210 is not adapted to perform stimulation.

Other types of electrochemical sensing probes may also be used in thisapplication, such as those detecting the presence of lactate in theneural tissue. These chemical markers may also be indicators of abnormalmetabolism and perfusion levels.

A lead 1310 with four ring electrodes 1312 is illustrated in FIG. 13. Inaddition to traditional electrographic sensing and electricalstimulation as described above, the lead 1310 can be used to measurelocal perfusion by impedance imaging. Accordingly, low current and shortpulses of electrical stimulation (to avoid undesired depolarization andelectrographic interference artifacts, and to improve battery life) areapplied and impedance is measured between a pair of electrodes 1312 onthe lead 1310. Impedance imaging techniques such as plethysmography canbe performed, where the image is constructed in two dimensions. Thesemethods may also be termed impedance tomography or ECCT (electriccurrent computed tomography).

As with other measurements described herein, electrical impedanceplethysmography is advantageously used in a relative comparison tobaseline measurements, rather than as an absolute value. Further,compensation for routine heart rhythm based variations (by takingaverage or peak values over several measurements) is also deemedadvantageous.

With a sufficient number of electrodes disposed around a target site, itis possible to use a series of impedance measurements between differentsets of electrodes to reconstruct a tomographic image of blood flow;techniques for accomplishing electrical impedance tomography are wellknown. In a presently preferred embodiment, data is collected fortomographic measurements by the device 110 and transferred to theprogrammer 312 or other external apparatus, where the intensivecomputations needed to reconstruct visualizations are more feasiblycarried out.

FIG. 14 illustrates a sample hypothetical graph of cerebral perfusionmeasurements. At its start 1412, a perfusion curve 1410 (not illustratedto any particular scale) is approximately centered between an upperthreshold 1414 and a lower threshold 1416. The perfusion curve 1410shows gradually increasing perfusion up to a first time 1418, at whichthresholds 1414 and 1416 are recalculated to accommodate long termtrending. The thresholds 1414 and 1416 are recalculated again at asecond time 1420, and shortly thereafter at a third time 1422 and thecurve 1410 starts to drop below the lower threshold 1416. This dropbelow an adjusted threshold indicates, in an exemplary system or method,an undesired drop in perfusion, indicating that a therapeutic actionshould be taken as discussed in connection with the flow chart of FIG.15 below. In an embodiment, cerebral blood flow is directly modulated(by means described herein) to increase it above the threshold 1416, orother actions may be taken alone or in conjunction with blood flowmodulation.

During the time period 1422 the curve 1410 is below the lower threshold1416, the thresholds 1414 and 1416 are not recalculated. Thresholds arereadjusted periodically, e.g., step 1524 (in a preferred embodiment, aselectable number of seconds must pass before the readjustment occurs).

In one embodiment, the curve 1410 represents a condition which iscalculated from the ratio of two or more measures, where one of themeasures is representative of a characteristic of tissue that isrelatively proximate to the location of a neurological event such as aseizure focus (i.e., an associated area), and where the other measuresare representative of a characteristic of tissue that is relativelydistal to the location of a neurological event (i.e., non-associatedarea), for example, outside of the focus of epileptiform activity. Forexample, the condition can be calculated as the ratio between perfusionin the region of a seizure focus and perfusion in a contralateral area.Alternatively, the condition can be calculated as the ratio betweenspectral power in a selected high frequency range in the region of aseizure focus and a measurement of this power at multiple probes whichsense activity from regions located more distal to the focus. Further,the condition can be calculated with respect to norm data, such asself-norm data. For example, the curve 1410 can represent the currentHbO₂ relative to the average (HbO₂+HbR) value for the last hour. NIRSdata can be combined with, or measured in relation to, pulse oximetry,such as only measuring NIRS data at the peak of the EKG. Further,central NIRS data can be measured in the context of other measurement ofarterial oxygen saturation, or other arterial gas estimations,measurements of trancutaneous oxygen and carbon dioxide, measures ofsystemic circulation as monitored by electrocardiograph and invasive ornon-invasive blood monitors, in order to obtain a measurement ofperipheral changes which can affect central NIRS readings. In otherwords, NIRS data and changes can be evaluated relative to peripheralchanges in order to provide more accurate sensing and decrease falsedetections. The condition can be calculated based upon the changedetected centrally, in the brain, with respect to a peripheral change.The condition representing a brain measurement can be calculated as aratio including, for example, heart rate or blood pressure. Thecondition can also be assessed conditionally, for example, the curve1410 is only assessed when peripheral measurements have certain values.For example, when a posture/position measurement indicates that apatient has transitioned from lying down to standing up, the baselinemay be recomputed, and the curve 1410 is not reassessed until aspecified duration, e.g., 20 seconds, has elapsed.

The condition in the signal being sensed 1410 can be additionallyevaluated by evaluating temporal changes in a manner other than usingthresholds (or guard bands) as shown in FIG. 14. For example, the rateof change of the signal, as reflected in the slope, can be evaluated,wherein when the slope is above a specified level, for a specifiedamount of time, then stimulation occurs. Other measures that may be usedto evaluate the temporal patterns that characterize the condition of thesignal being measured 1410 include those usable to analyze biologicalresponses such as Galvanic skin response (e.g., time until, or value at,half-maximum which occurs after an event, total area under the curveover time). The condition of the signal being computed can be thez-transform of a measure of the signal, wherein, for example, any valueover 2 or under −2 indicates that a statistically significant change hasoccurred.

In FIG. 14, the guard bands (thresholds) are recalculated at certainspecified times. The guard bands can also be recalculated based upon thesignal 1412 being evaluated. In other words, the duration of the windowin which the guard bands are calculated can be adaptively defined basedupon the characteristics of the sensed data. In one example, of thechange in the signal 1410 is larger, then the duration of the window maybe decreased according to a rule. For example, for every increase of Xunits in signal amplitude, the duration of the window is decreased by Ypercent. The signal 1410 can also be used to change the post-eventwindow used in subsequent analysis of activity. For example, as shown inFIG. 16, the duration of the guard bands can be based upon the signal.In FIG. 16, guard bands 1610 and 1616 occur first and then are followedby bands 1614 and 1620. When the exemplary signal 1630 is sensed, thenthe slope of the descent combined with the total descent of the curve issmall enough that it causes the pre-drop guard bands to be recalculatedon data in the sensed signal 1630 which spans across the durations 1612and 1614, and the durations 1616 and 1620. When the sensed signal islike the signal 1632, then the change is significant enough that anevent is detected without recalculation of the guard bands. In thismanner, the amount of data used to calculate the guard bands can beadjusted based upon the measurement of the signal itself and thereforethe detection of events occurs adaptively. Additionally, the length ofthe data which is examined in the post-event period can be based uponthe characteristics of the event. For example, curve 1632 has a changethat is large enough that the guard bands 1622 and 1626 are utilized. Ifa seizure-related change in perfusion is going to occur, it will do sotemporally close to the event just detected. If curve 1630 occurs, thenthe calculation of guard bands may occur using a longer period.Additionally, the guard bands can be applied to other data being sensed.For example, if the data sensed is like the curve 1630, rather than likethe curve 1632, then the post-event time for which a specific EEGcriterion may be activated may be made longer or shorter. Alternatively,different EEG detection algorithms can be invoked based upon thecharacteristics of the signals 1630 and 1632.

A method according to the invention is performed, as illustrated in FIG.15, by initializing a perfusion trend value (step 1510). This isperformed by performing an initial perfusion measurement (or average ofa sequence of measurements) and storing it in a trend variable.

Perfusion at a desired site is then measured (step 1512) by one of themethods described herein or any other applicable technique. Themeasurement is then compared (step 1514) to the previously calculatedtrend. If the perfusion measurement exceeds an upper bound (step 1516),namely the trend value plus an upper threshold value (or in analternative embodiment, the trend value multiplied by an upper thresholdfactor generally greater than one), then a first action is performed(step 1518). This condition, when the perfusion exceeds a threshold,indicates hyperperfusion that may be an undesired or pathologicalcondition, or at least an indication that conditions are out ofequilibrium and require therapeutic intervention.

To treat hyperperfusion, stimulation may be applied to the patient'scaudate nucleus; stimulating other anatomical targets may also serve todecrease perfusion. An audio alert, somatosensory stimulation, or otherindication may also be provided to the patient or a caregiver via theimplantable neurostimulator device 110 or its communication subsystem530 (FIG. 5).

If the perfusion measurement exceeds (i.e., is lower than) a lower bound(step 1520), namely the trend value minus a lower threshold value (or inan alternative embodiment, the trend value multiplied by a lowerthreshold factor generally less than one), then a second action isperformed (step 1522). This condition, when the perfusion is lower thana threshold, indicates hypoperfusion that may be an undesired orpathological condition suggestive of an imminent epileptic seizure.Hypoperfusion may be treated by applying stimulation at or near the sitewhere the hypoperfusion was observed. In the case of epilepsy,frequently this will be a seizure focus. As with hyperperfusion,feedback may be provided to the patient or caregiver. Alternatively,external therapy (such as transcranial magnetic stimulation) may beapplied, either automatically or manually (based on an indication).

As set forth above, for either hyperperfusion or hypoperfusion,stimulation of a variety of anatomical targets may be performedaccording to the invention to produce beneficial changes in corticalblood flow to treat neurological disorders. Specifically, but not by wayof limitation, potential stimulation targets include the cortex of thebrain (including specialized structures such as the hippocampus), whitematter, basal ganglia (including the caudate nucleus), the brain stem,the spinal cord, the cerebellum or any of various cranial or peripheralnerves including the vagus nerve. Somatosensory stimulation (includingsound, vision, and touch) may be suitable in some circumstances,particularly for acute therapy.

If the perfusion is within bounds, the trend variable is updated (step1524) preferably periodically as described above. The method proceeds byrepeating a perfusion measurement (step 1512) and continuing.

The actions taken need not be therapeutic in nature; they may serveother purposes. In one embodiment, the implantable device 110 isessentially a seizure counter adapted to identify and collectinformation about periods of abnormal perfusion for later retrieval.

The flow chart of FIG. 15 is not an exclusive description of methodsperformed by a system according to the invention. Rather, it describes asingle aspect of a single embodiment of a system according to theinvention for observing blood flow and taking action in response tochanges. This method may be performed in conjunction with, or inparallel with, other methods generally performed by implantable devicesand implantable neurostimulators specifically. In particular, cerebralblood flow management may be considered a useful adjunctive therapy foran implanted responsive neurostimulator such as that described in U.S.Pat. No. 6,810,285 to Pless et al., referenced above, that is alsocapable of applying pulsatile electrical stimulation in response todetected abnormal electrographic activity.

One possible clinical scenario is as follows. Consider a patient inwhich hypoperfusion is exhibited on the side of the brain where thepatient's epileptiform activity originates. In the contralateral side,perfusion may be normal. This is considered to be a likely scenario,though by no means the only possible scenario. Some time before anepileptic seizure is likely to occur, perfusion starts to rise in theepileptic hemisphere, and plunges abruptly in the contralateralhemisphere just prior to the seizure. In this scenario, two parallelcourses of the flow illustrated in FIG. 14 are contemplated, each onemeasuring perfusion in an area of interest in opposite hemispheres.

Interictally, while perfusion is low in the epileptic (hypoperfused)hemisphere, a system can be programmed to deliver electrical stimulationto increase perfusion and normalize the system. Each burst ofstimulation tends to have a short term effect. Stimulation may beprovided intermittently but regularly, while perfusion is monitored. Ifperfusion rises beyond the amount caused by the interictal stimulation,and especially if it is accompanied by a drop in perfusion in thecontralateral hemisphere, then seizure activity may be anticipated.Accordingly, the stimulation strategy is altered in light of the changedbrain state, and an alternative course of therapy is initiated, whichmay include some or all of the following: (1) stimulation of the caudatenucleus to decrease excitability in the epileptic hemisphere; (2)stimulation of the cortical or sub-cortical structures of thecontralateral hemisphere to increase perfusion there; and (3)therapeutic electrical stimulation to reduce the likelihood of seizureactivity. If ictal electrographic activity is then also observed in asystem, further actions may also be taken. Different actions may also betaken depending on whether the patient is asleep or awake (aspotentially indicated by electrographic activity) or based on othermeasures of level of arousal or activity, as these factors may also tendto affect perfusion.

It should be observed that while the foregoing detailed description ofvarious embodiments of the present invention is set forth in somedetail, the invention is not limited to those details and an implantablemedical device or system made according to the invention can differ fromthe disclosed embodiments in numerous ways. In particular, it will beappreciated that embodiments of the present invention may be employed inmany different applications to responsively treat epilepsy and otherneurological disorders. It will be appreciated that the functionsdisclosed herein as being performed by hardware and software,respectively, may be performed differently in an alternative embodiment.It should be further noted that functional distinctions are made abovefor purposes of explanation and clarity; structural distinctions in asystem or method according to the invention may not be drawn along thesame boundaries. Hence, the appropriate scope hereof is deemed to be inaccordance with the claims as set forth below.

1. A method for responding to a neurological disorder in a human patientcomprising: obtaining a perfusion measurement with an implantabledevice; identifying a change in the cerebral perfusion measurement; inresponse to the change, performing an action; and identifying astructure in a hemisphere demonstrating increased blood flow, andwherein performing the action comprises stimulating a neural structurein a hemisphere contralateral to the hemisphere demonstrating astructure with the increased blood flow.
 2. A method for responding to aneurological disorder in a human patient comprising: obtaining aperfusion measurement with an implantable device; identifying a changein the cerebral perfusion measurement; and in response to the change,performing an action, wherein obtaining the cerebral perfusionmeasurement comprises: observing a first signal from a first implantedsensor; observing a second signal from a second implanted sensor; andcalculating the perfusion as a composite of the first signal and thesecond signal, wherein the first implanted sensor is positioned tomeasure the first signal from an artery feeding a location and thesecond implanted sensor is positioned to measure the second signal froma vein leaving the location.
 3. A method for responding to aneurological disorder in a human patient comprising: obtaining aperfusion measurement with an implantable device; identifying a changein the cerebral perfusion measurement; and in response to the change,performing an action, wherein obtaining the cerebral perfusionmeasurement comprises: observing a first signal from a first implantedsensor; observing a second signal from a second implanted sensor; andcalculating the perfusion as a composite of the first signal and thesecond signal, wherein performing the action comprises: delivering atherapy to modulate the cerebral perfusion measurement, whereindelivering the therapy causes the first signal to more closely resemblethe second signal.